Human Interferon-γ mRNA Autoregulates Its Translation through a Pseudoknot that Activates the Interferon-Inducible Protein Kinase PKR

  title={Human Interferon-$\gamma$ mRNA Autoregulates Its Translation through a Pseudoknot that Activates the Interferon-Inducible Protein Kinase PKR},
  author={Yitzhak Ben-Asouli and Yona Banai and Y Pel-Or and Alexei Shir and Raymond Kaempfer},

Figures from this paper

Interferon- mRNA attenuates its own translation by activating PKR: A molecular basis for the therapeutic effect of interferon- in multiple sclerosis

It is proposed that the therapeutic effect of IFN-β in multiple sclerosis may rest, at least in part, on its exquisite ability to induce high levels of PKR in the cell and thereby to limitIFN-γ mRNA translation through this negative feedback loop, blocking the excessive IFN -γ gene expression that precedes clinical attacks.

Dynamic refolding of IFN-gamma mRNA enables it to function as PKR activator and translation template.

Through gain-of-function mutations, it is shown that the RNA activator can adopt alternative conformations that activate PKR, and which thus prevents overexpression of this inflammatory cytokine.

Control of mRNA Splicing by Intragenic RNA Activators of Stress Signaling: Potential Implications for Human Disease

In conclusion, intragenic elements of 100–200 nucleotides in length within primary transcripts of cellular genes, exemplified by the tumor necrosis factor (TNF)-α gene and fetal and adult globin genes, are capable of forming RNA structures that potently activate PKR and thereby strongly enhance mRNA splicing efficiency.

Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA.

A region of the viral RNA comprising part of the internal ribosome entry site (IRES) is able to bind to PKR in competition with double-stranded RNA and can prevent autophosphorylation and activation of the kinase in vitro, suggesting a dual function for the viral IRES.

Transcript-Selective Translational Silencing by Gamma Interferon Is Directed by a Novel Structural Element in the Ceruloplasmin mRNA 3′ Untranslated Region

A minimal, 29-nucleotide element was determined by gel shift assay to be sufficient for maximal binding of the IFN-γ-activated inhibitor of translation (GAIT), an as-yet-unidentified protein or complex.

Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative Action

A detailed picture is provided on how signaling downstream of PKR unfolds and what are the ultimate consequences of the antiproliferative and antiviral effects exerted by interferons.



The Interferon-inducible Protein Kinase PKR Modulates the Transcriptional Activation of Immunoglobulin κ Gene (*)

expression of wild type PKR and a catalytically inactive dominant negative PKR mutant in the murine pre-B lymphoma 70Z/3 cells demonstrate that there are at least two distinct PKR-mediated signal transduction pathways to the transcriptional machinery depending on cell type and stimuli, NF-κB-dependent and NF-γB-independent.

In vitro activation of the interferon-induced, double-stranded RNA-dependent protein kinase PKR by RNA from the 3' untranslated regions of human alpha-tropomyosin.

  • S. DavisJ. Watson
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1996
It is reported that purified RNA from the 3' untranslated region of human alpha-tropomyosin can inhibit in vitro translation in a manner consistent with activation of PKR, suggesting that activation ofPKR could be the mechanism by which tropomyos in 3'UTR RNA exerts its tumor-suppression activity in vivo.

A cis-acting element in the 3'-untranslated region of human TNF-alpha mRNA renders splicing dependent on the activation of protein kinase PKR.

PKR and the 3' UTR interact during mRNA splicing to confer a novel type of regulation on expression of the TNF-alpha gene.

Physical association between STAT1 and the interferon‐inducible protein kinase PKR and implications for interferon and double‐stranded RNA signaling pathways

It is reported that PKR is involved in IFN‐ and dsRNA‐signaling pathways by modulating the function of the signal transducer and activator of transcription STAT1 and associates with STAT1 in mouse and human cells and indicates that there is a concomitant decrease in PKR–STAT1 interaction and increase in STAT1 DNA binding in response to IFNs or ds RNA.

HIV-1 TAR RNA has an intrinsic ability to activate interferon-inducible enzymes.

Chemically synthesized TAR mimicked other dsRNA species in its ability to activate and inhibit PKR at low and high RNA concentrations, respectively, suggesting an escape mechanism for the virus.

Inhibition of Double-Stranded RNA-Dependent Protein Kinase PKR by Vaccinia Virus E3: Role of Complex Formation and the E3 N-Terminal Domain

It is proposed that effective inhibition of PKR in yeast requires formation of an E3-PKR-dsRNA complex, in which the N-terminal half of E3 physically interacts with the protein kinase domain ofPKR.

Malignant transformation by a mutant of the IFN-inducible dsRNA-dependent protein kinase.

The double-stranded RNA-dependent protein kinase (dsRNA-PK) is thought to be a key mediator of the antiviral and antiproliferative effects of interferons (IFNs). Studies examining the physiological

Double-stranded RNA-activated protein kinase mediates virus-induced apoptosis: a new role for an old actor.

  • R. Kaufman
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
Two studies show that reduction in PKR level acts to delay cell death and thereby converts a lytic infection by encephalomyocarditis virus (EMCV) into a persistent infection, and suggest that modification of PKR function in vivo may be a feasible approach to influence viral pathogenesis.

Binding of the protein kinase PKR to RNAs with secondary structure defects: role of the tandem A-G mismatch and noncontiguous helixes.

In vitro selection experiments found that selected RNAs are able to activate or repress wild-type PKR autophosphorylation as well as its phosphorylation of protein synthesis initiation factor eIF-2, suggesting full-length PKR can bind to and be regulated by RNAs containing a tandem A-G mismatch.